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Патент USA US3024254

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V
3&24244
Patented Mar. 6, 1962
1
2
3,024,244
These 1,4-disubstituted butanone-2 compounds have the
following structure:
PROCESS FOR PRQDUCING PYRHDOXINE
AND INTERMEDIATES
Peter ll. Pollak, Scotch Plains, NJL, assignor to Merck 8.:
Co. line, Railway, N.J., a corporation of New Jersey
No Drawing. Application Oct. 17, 1957, Ser. No.
690,635, now Patent No. 2,948,733, dated Aug. 9, 1960,
which is a division of application Ser. No. 621,983,
Nov. 14, 1956, now Patent No. 2,904,551, dated Aug.
l7, 1957. Divided and this application Oct. 19, 1959,
Ser. No. 847,052
U0
2 Claims. (Cl. 260-295)
This application is a division of my co-pending ap
H
0
plication Serial No. 690,635 (now US. Patent No.
2,948,733), ?led October 17, 1957 which in turn is a 15 wherein R’ is alkyl, aryl, aralkyl or acyl, to produce a
division of my application Serial No. 621,983, now US.
pyridine derivative having the following structure:
Patent 2,904,551.
‘
(IJHQOR'
This invention relates to processes for the production
of pyridoxine (i.e., vitamin B6), and it is also concerned
with the preparation of novel chemical compounds pro 20
C
ducedas intermediates in the synthesis of pyridoxine.
It isjan object of this invention to provide an economi
cal and convenient method for synthesizing pyridoxine,
and to provide a series of novel intermediates.
In preparing pyridoxine I utilize as one of the starting 25
materials, a derivative of pyruvic acid, which has the struc
ture formula--_
HgC-
30
——C OOR
N
wherein R and R’ are as above and R” is hydroxy or
amino. These compounds can readily be converted to
35
wherein X is carb-alkoxy or cyano and Y is hydroxy or
cyano.
pyridoxine.
Alternatively, the pyruvate derivative, the glyciuate
ester and the 1,4-disubstituted butanone-2 compound can
be reacted simultaneously to form the pyridine derivative
described above.
In accordance with one embodiment of this invention,
The above compound is reacted with a glycinate ester 40 ethyl pyruvate, sodium bisul?te, sodium cyanide and ethyl
which has the formula—
glycinate are reacted to form ethyl-a-carbethoxymethyl
amino-a-methylcyanoacetate. The latter compound is
reacted with 1,4-dimethoxybutanone-2 and 2-methyl-3
CHzCOOR
N
hydroXy-4,5-bis(methoxymethyl)-6-carbethoxypyridine is
recovered.
wherein R is a lower alkyl group to form a compound of 45
formula
‘
This latter compound is acidi?ed with dilute hydro
chloric acid and heated in an autoclave at elevated tem
peratures to form pyridoxine hydrochloride.
The synthesis of pyridoxine and the novel intermedi
ate chemical compounds obtained and the process may
50
be illustrated by the following speci?c examples.
It
should be noted, of course, that these examples are in—
tended to be illustrative of the methods and procedures
utilized in preparing these compounds and that it is not
intended to be restricted or to be regarded as embodying
55 the only Way in which my novel chemical compounds may
be formed and recovered.
Example 1
wherein X and R are as above.
The above compound is reacted with a 1,4-disubstitut
H
ed butanone-2 ether in which both hydroxyl groups are 60 H5C20—C
etheri?ed, either with lower alkyl groups such as methyl
H;C——C
or ethyl, aryl or aralkyl groups such as benzyl or esteri?ed
with acyl groups such as acetyl or benzoyl to form the
straight-chain dimethyl, diethyl, dibenzyl or diacetyl
derivatives of 1,4-disubstituted butanone-Z or in which 65
both hydroxyl groups are etheri?ed with each other to
form a cyclic inner ether, i.e., 3-keto-tetrahydrofurane.
CHz-O O 0 02115
+N
|
H:
(EH20 CHrCaHs
CH;
3,024,244
4
brown residue was recrystallized from hot water to yield
Example 1-Continued
pyridoxine hydrochloride.
CHzO CHaCeHi
-—)
HO-C
% \
HgC~C
Example 3
C-~CH2QCH2CgHi -——+
CHn-COOCzH;
—COOC2H5
\
+ NaCN + III
H:
(IJH2OH
/ \
HO—C/
HsC-C
\N/
10
C-CHiOH
H
C-H
(IJHaOCH;
+ CO:
CnHrOH
ZCnHrCHaOH 15
.1101
116 parts of ethyl pyruvate and 103 parts of ethyl
glycinate were dissolved in anhydrous methyl alcohol
containing a trace of anhydrous hydrochloric acid. After
standing at ambient temperature for 2 hours, the solvent 20
was removed by vacuum distillation and a viscous oil
of ethyl-a-carbethoxymethyliminopyruvate was recovered.
N
/
C-CHaOCH;
t
(.FHQOCH]
/C\
HO-C
c-o1noon. +
\
HgC-
\ %
offlglgNé
C—COOC2H5
N
onion
201 parts of the ethyl-a-carbethoxymethyliminopyru
vate and 284 parts of 1,4-dibenzyloxybutanone-2 were
0
dissolved in anhydrous methyl alcohol. To this solution 25
was added 25 parts of anhydrous sodium carbonate and
the mixture was agitated at 50° C. for 12 hours in a
HO~C
rec-o
nitrogen atmosphere. The solvent was removed by
vacuum distillation. The residue contained 2-methyl-3
/ \
\ %
C-CHrOH
0-H
N
hydroxy-4,5-bis (benzyloxymethyl ) -6-carbethoxy-pyridine.
197 parts of the bisul?te addition product of ethyl
The 2 - methyl-3-hydroxy-4,5 -bis(benzyloxymethyl)
pyruvate, 30 parts of sodium bisul?te, 50 parts of sodium
G-carbethoxy-pyridine thus obtained was acidi?ed with di
cyanide, and 103 pants of ethyl glycinate were dissolved
lute hydrochloric acid. To the resulting solution was
in water. After 8 hours standing at room temperature,
added 2 parts of charcoal and the mixture was agitated
an oily layer was separated. The aqueous layer Was ex
35
and then ?ltered. The ?ltrate was placed in an autoclave
tracted with ether. The ether extracts were combined
and the temperature maintained at 155° C. for three
with the oil and dried over sodium sulfate and distilled to
hours. After vacuum dehydration, the amorphous brown
yield ethyl - or - carbethoxyrnethylarnino-a-methylcyano
residue was recrystallized from hot water to yield pyri
acetate.
doxine hydrochloride.
228 parts of ethyl-a-carbethoxymethylamino-a-methyl
cyanoacetate and 132 parts of 1,4-dimethoxybutanone-2
Example 2
were dissolved in anhydrous pyridine to which was added
5 parts of dry sodium methoxide. After 24 hours the
mixture was vacuum distilled to dryness to form a brown
oily residue containing 2-methyl-3-hydroxy-4,5-bis (meth
H]
oxymethyl) ~6-carbethoxypyridine.
l
Water was added to the brown oily residue of Z-methyl
0
3 - hydroxy-4,5-bis(rnethoxymethyl)-6-carbethoxypyridine
011,0 0,115
/(l3\
rho-(i
C-CH2O 0,115
0-00 0 01m
\N¢
and charcoal was added to the aqueous suspension. The
mixture was ?ltered. The ?ltrate was acidi?ed with
dilute hydrochloric acid and heated in an autoclave to
155° C. for three hours. Charcoal was added to the re
action solution and the mixture was ?ltered. The ?ltrate
was vacuum concentrated to dryness. The resulting crys
55 talline solid was recrystallized from hot water. The crys~
tals melted at 205~206° C. ad were identi?ed as pyri
doxine hydrochloride.
60
116 parts of ethyl pyruvate, 103 parts of ethyl glycinate
and 160 parts of 1,4-diethoxybutanone-2 were dissolved
in anhydrous methyl alcohol. To this solution was added
20 parts of anhydrous sodium carbonate and the mixture
was agitated at 50° C. for 12 hours in a nitrogen atmos
65
phere. The solvent is removed by vacuum distillation to
form a residue of 2-methyl-3-hydroxy - 4,5 - bis(ethoxy
methyl) -6-carb ethoxypyridine.
The crude residue of 2-methyl-3~hydroxy-4,5-bis(eth
oxymethyl)-6-carbethoxy pyridine thus obtained was acidi 70
?ed with dilute hydrochloric acid. To the resulting solu
tion was added 2 parts of charcoal and the mixture was
agitated and then ?ltered. The ?ltrate was placed in an
autoclave and the temperature maintained at 155° C. for
three hours. After vacuum dehydration, the amorphous 75
N
3,024,244
6
5 parts of dry sodium methoxide.
After twenty-four
hours at room temperature the mixture was vacuum
distilled to dryness. The brown oily residue contained
2-methyl-3-hydroxy-4,S-bis(methoxymethyl-6-carbethoxy
pyridine. Water was added to the 2-methyl-3-hydroxy
4,5-bis (methoxymethyl) -6-carbethoxypyridine oily residue
and charcoal was added to the resulting aqueous suspen
sion. The mixture was ?ltered. The ?ltrate was acidi?ed
with dilute hydrochloric acid and heated in an auto
197 parts of the bisul?te addition product of ethyl 10 clave to 155° C. for 3 hours. Charcoal was added to
pyruvate and 103 parts of ethyl glycinarte were dissolved
the resulting solution and the mixture is ?ltered. The
in anhydrous diethyl ether containing 30 parts of anhy
?ltrate was vacuum concentrated to dryness. The result
drous calcium chloride. The mixture was allowed to
ing crystalline solid was recrystallized from hot water.
stand at room temperature for 2 hours. The mixture
The crystals melted at 205~206° C. and were identi?ed
was ?ltered and the solvent removed in vacuo to yield 15 as pyridoxine hydrochloride.
an oily product of ethyl - a - carbethoxymethylimino
pyruvate.
Example 6
201 parts of ethyl u-carboethoxymethyliminopyruvate
thus obtained and 284 parts of 1,4-dibenzyloxybutanone
H
2 were dissolved in anhydrous methyl alcohol. To this 20 H5C20——C
solution was added 30 parts of anhydrous sodium carbo
/
CH2-—COOC2H&
nate and the mixture was agitated at 50° C. for 12 hours
in a nitrogen atmosphere. The solvent was removed
CHnO C2115
by vacuum distillation to yield 2-methyl-3-hydroxy-4,5
bis (benzyloxymethyl) -6-carbethoxypyridine.
C1120 02115
|
CH2
25
\
The residue of 2-methyl-3-hydroxy-4,5-bis(benzyloxy
C——CH2O C2H5 ———>
methyl)-6-carbethoxypyridine was acidi?ed with dilute
hydrochloric acid. To the resulting solution was added
C-COO CaHa
2 parts of charcoal and the mixture was agitated and
then ?ltered. The ?ltrate was placed in an autoclave 30
and the temperature maintained at 155° C. for 3 hours.
(IIH2OH
C
After vacuum dehydration the amorphous ‘brown residue
was recrystallized from hot water to yield pyridoxine
hydrochloride.
35
Example 5
ll
115020-43
HaC-
CH:—C 0 0 0211.
+ NBHSO; + NECN + N
|
197 parts of the bisul?te addition product of ethyl
pyruvate, 103 parts of ethyl glycinate and 160 parts of
1,4~diethoxybntanone~2 were dissolved in anhydrous
40 methyl alcohol. To this solution was added 15 parts of
anhydrous sodium carbonate and the mixture was agi
tated at 50° C. for 12 hours in a nitrogen atmosphere.
The solvent was removed by vacuum distillation and the
residue contained 2~methy1 - 3 - hydroxy-4,5-bis(ethoxy
N
4
methyl)-6-carbethoxy pyridine.
The 2 - methyl-3-hydroxy-4,5-bis(ethoxymethyl)-6-car
|
H
\bethoxy pyridine was acidi?ed with hydrochloric acid.
To the resulting solution was added 2 parts of charcoal
and the mixture was agitated and then ?ltered. The
50 ?ltrate was placed in an autoclave and the temperature
maintained at 155° C. for three hours. After vacuum
dehydration, the amorphous brown residue was recrys
tallized from hot water to yield pyridoxine hydrochloride.
Example 7
55
omo o 0 0H,
Natl:
CHT'COOC?Hb (I)
Had-o
\
60
0
+ N
l
a
C~CH2O o 0 0H,
Ha
[I
_
0
(‘11110 e 0 CH;
0
116 parts of ethyl pyruvate, 120 parts of sodium bi
sul?te, 52 parts of sodium cyanide, and 103 parts of 65
ethyl tglycinate were dissolved in water. After 8 hours
standing at room temperature, an oily layer was sepa
rated and the aqueous layer was extracted three times
with 100 parts of diethyl ether. The ether extracts were
combined with the oil and dried over sodium sulfate and 70
distilled to yield ethyl u-carbethoxymethylamjno-u-meth
ylcyanoacetate.
228 parts of ethyl a-carbethoxymethylamino-a-methyl
cyanoacetate and 132 parts of 1.,4-dimethoxybutanone-2
were dissolved in anhydrous pyridine to which was added 75
/ \
HzN-(?
NaONO
(‘J-C1110 o 0 on, ---->
mo-o
(3
%
o-oo 0 02H.
{131110 c 0 0H,
110-0
/ \
HaC--O
o-wmocoon3
o-o 0 0 our,
\N%
l
3,024,244
8
was recrystallized from hot water to yield pyridoxine
Example 7—Continued
onion
/C\
110-0 \C—CHaOH
H
rho-c
l
CH
hydrochloride.
ExampleQ
5
+ 2011300011
CaHgOH + 001
CHz-OO O 02H;
\ %
N
.1101
10
69 parts of acetyl cyanide, 103 parts of ethyl glycinate
and 188 parts of 1,4-diacetoxybutanone~2 were dissolved
in anhydrous dioxane. To this solution was added 1
part of powdered sodium hydroxide and the mixture was
agitated at room temperature for 24 hours. The solvent 15
CH1
,
was removed by vacuum distillation to form a resi
due containing 2-methyl-3-amino-4,5-bis(acetoxymethyl)
6-carbethoxypyridine.
To the residue of 2-methyl~3-hydroxy-4,5-bis(acetoxy
methyl)-6-carbethoxypyridine was added hydrochloric
acid. 69 parts of sodium nitrite were then added at 75°
C. and the resulting solution placed in an autoclave at
155° C. for three hours. After autoclaving the solution
was mixed with 1 part of charcoal. The mixture was
?ltered and the vacuum ?ltrate concentrated to dryness. 25
The residue was recrystallized from hot water to yield
l
0-0 0 0 02H;
pyridoxine hydrochloride.
%
30
To an ether solution of 69 parts of acetyl cyanide was
added 120 parts of sodium bisul?te and 52 parts of sodium
cyanide. After ?ve hours of agitation at room tempera
ture, this mixture was ?ltered. The ?ltrate contained
40
the bisul?te addition product of ethyl pyruvate.
To the bisul?te addition product of ethyl pyruvate
?ltrate was added 103 parts of ethyl glycinate and 10
parts of piperidinium acetate. This solution was re?uxed
on a steam ‘bath for 12 hours. The ether was then re
45 moved by distillation and the residue contained a-car
bethoxymethylamino-a-methylmalononitrile.
This residue was dissolved in anhydrous ether and 86
parts of 3-ketotetrahydrofurane was added to the mixture
in the presence of trimethylbenzyl ammonium hydroxide
50 at re?ux temperature for a period of 40 hours. The ether
was removed by distillation leaving 6-methyl-7-amino
4-carbethoxy-l ,3-dihydrofuro [3,4-c] pyridine.
This residue was acidi?ed with dilute hydrochloric
acid. 569 parts of sodium nitrite were then added and
the mixture heated at 75° C. for three hours to form
6 - methyl - 7 - hydroxy - 4 - carbethoxy - 1,3 - dihydro
69 parts of acetyl cyanide were dissolved in anhydrous
pyridine and 103 parts of ethyl glycinate were added.
furo [3,4»c]pyridine.
The solution was autoclaved and then charcoal was
added to the mixture. The mixture was ?ltered and the
After standing for four hours at room temperature the
vacuum ?ltrate concentrated to dryness. The residue
solvent was distilled from the mixture to yield an oil 60 was recrystallized from hot water to yield pyridoxine
containing a-carbethoxymethylimino-propionitrile.
This oil was dissolved in anhydrous ether and 86 parts
of 3-ketotetrahydrofurane was added to the mixture in
the _presence of trimethylbenzylammoniumhydroxide.
The mixture was heated at re?ux temperatures for a
period of 40 hours. The ether was removed by distilla
tion to yield a residue containing 6-methyl-7-amino-4
carbethoxy-l,3-dihydrofuro-[3,4-c]Pyridine.
This residue was acidi?ed with dilute hydrochloric
acid. 69 parts of sodium nitrite were added to the mix 70
ture and it was heated at 75° C. for three hours to form
6 - methyl - 7 - hydroxy - 4 - carbethoxy - 1,3 - dihydro
furo-[3,4-c]pyridine.
The solution was autoclaved and
then charcoal was added. The mixture was ?ltered and
the vacuum ?ltrate concentrated to dryness. The residue 75
hydrochloride.
3,024,244
10
Example 10-Continued
Ere-r
HBO-C
\ ¢
this compound with B-keto'tetrahydrofurane and heating
BIO-p.’
/O\ /CH:
‘r
r
wherein R is a lower alkyl group, intimately contacting
to form a pyridine derivative of the formula
Na ONO
/C\\ /CHs
-> HO-t ‘f
C-GOOCgHg
HgC-C
N
\ %
H:O——-—(|)
C-COOCaH:
/C\ CH:
eN-t \‘E0-0001:
Inc-d
N
(IIHQOH
0
HO-C
HgC-C
/ \
%
10
O-OH2OH + 00, + CaiHaOH
CH
treating this product with sodium nitrite in the presence
of hydrochloric acid, and subjecting the resulting reaction
product to acid hydrolysis at elevated temperature and
pressure to produce pyridoxine.
173 parts of the bisul?te addition product of acetyl 15 2. A process which comprises intimately contacting a
cyanide were suspended in anhydrous pyridine and treated
pyruvic acid derivative of the formula
with 103 parts of ethyl glycinate. After four hours
standing at room temperature the ether was distilled to
N
yield an oil containing u-carhethoxymethylamino-a
methylmalononitrile.
This oil was dissolved in anhydrous ether and treated
with 86 parts of S-ketotetrahydrofurane in the presence
of trimethylbenzyl ammonium hydroxide at re?ux tem
peratures for a period of 40 hours to form 6-methyl-7
amino-4-carbethoxy-1,S-dihydrofuro-[3.4-c]pyridine. The
ether is removed by distillation and the residue is treated
in accordance with the procedure given in Example 9
20
with a lower alkyl ester of glycine to form an inter
mediate of the formula
ON
H3C—-(lJ—-CN
25
N-OHzCOOR
1'1
to give pyridoxine hydrochloride.
Various changes and modi?cations may be made in
carrying out the present invention Without departing from 30 wherein R is a lower alkyl group, intimately contacting‘
this compound with 3-ketotetrahydrofurane and heating
the spirit and scope thereof. Insofar as these changes
to form a pyridine derivative of the formula
and modi?cations are within the purview of the annexed
claims, they are to be considered as part of this invention.
H2C——O
1 claim:
(I) 6112
HzN—-C/ \O/
HaC—C N%é—000R
1. A process that comprises intimately contacting a 35
pyruvic acid derivative of the formula
40 wherein R is the same as above.
with a lower alkyl ester of glycine to form an inter
mediate of the formula
References Cited in the ?le of this patent
vUNITED STATES PATENTS
45
2,680,743
2,734,063
2,904,551
Stevens _____________ __ June 8, 1954
Stevens _____________ __ Feb. 7, 1956
Pollak ______________ __ Sept. 15, 1959
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